Cell-cell adhesion is essential for maintenance of tissue architecture;however, intercellular adhesion structures are not only the glue that keeps cells together. Cell-cell junctions also function as biosensors of external cellular environment that provide cells with information about the position and cellular identity of their neighbors. This information is later translated into important cell decisions concerning proliferation, differentiation or cell death. These lines of communication are broken or perturbed in cancer. While normal epithelial cells in culture are contact-inhibited and stop proliferating upon reaching the confluence, the cancer cells are not contact-inhibited and continue to grow past confluence. The molecular mechanisms connecting intercellular adhesion structures with regulation of cell accumulation are poorly understood. While cells use different types of cell-cell adhesion structures, the Adherens Junctions appear to be often perturbed in human cancers. The Adherens Junction proteins E-cadherin, 1-, and 2-catenins are often mutated in tumor cells, and loss of E-cadherin and 1E-catenin correlates with tumor aggressiveness and poor clinical outcome. Despite these phenotypic correlations, it is still unclear whether 1E- catenin is a tumor suppressor protein. In this application we propose to determine potential tumor-suppressor role of 1E-catenin using stem cell niche-specific knockout approach. We have evidence that deletion of 1E-catenin in skin hair follicle stem cell compartment results in development of completely penetrant skin tumors. We will analyze primary tumor initiating events in the stem cell niche of these mutant mice and reveal critical cellular and molecular events responsible for skin tumor development. In addition, we will study potential cooperation between 1E-catenin and other known tumor suppressors causally involved in skin tumor development and determine the signaling mechanisms responsible for tumor suppression function of 1E-catenin. These studies will help to extend our knowledge of tumor-suppressor proteins and mechanisms of their function. This information is critical for future development of efficient anticancer therapies. PUBLIC HEALTH RELEVANCE: Studies described in this project identify a novel tumor suppressor gene involved in mammalian skin cancer and propose to analyze its cellular and molecular mechanisms. Information obtained during this study will help to identify critical signaling pathways and molecules causally responsible for mammalian skin cancer. This knowledge is necessary for development of novel targeted therapies for treatment of skin cancer.